Context Clinical practice guidelines on the management of mineral and bone disorders due to chronic kidney disease recommend specific treatment target levels for serum phosphorus, parathyroid hormone, and calcium. Objective To assess the quality of evidence for the association between levels of serum phosphorus, parathyroid hormone, and calcium and risks of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease. Data Sources The databases of MEDLINE (1948 to December 2010) and EMBASE (1947 to December 2010) were searched without language restriction. Hand searches also were conducted of the reference lists of primary studies, review articles, and clinical guidelines along with full-text review of any citation that appeared relevant. Study Selection Of 8380 citations identified in the original search, 47 cohort studies (N = 327 644 patients) met the inclusion criteria. Data Extraction The characteristics of study design, participants, exposures, and covariates together with the outcomes of all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular events at different levels of serum phosphorus, parathyroid hormone, and calcium were analyzed within studies. Data were summarized across studies (when possible) using random-effects meta-regression. Data Synthesis The risk of death increased 18% for every 1-mg/dL increase in serum phosphorus (relative risk [RR], 1.18 [95% confidence interval {CI}, 1.12-1.25]). There was no significant association between all-cause mortality and serum level of parathyroid hormone (RR per 100-pg/mL increase, 1.01 [95% CI, 1.00-1.02]) or serum level of calcium (RR per 1-mg/dL increase, 1.08 [95% CI, 1.00-1.16]). Data for the association between serum level of phosphorus, parathyroid hormone, and calcium and cardiovascular death were each available in only 1 adequately adjusted cohort study. Lack of adjustment for confounding variables was not a major limitation of the available studies. Conclusions The evidentiary basis for a strong, consistent, and independent association between serum levels of calcium and parathyroid hormone and the risk of death and cardiovascular events in chronic kidney disease is poor. There appears to be an association between higher serum levels of phosphorus and mortality in this population.

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Serum Levels of Phosphorus, Parathyroid Hormone, and Calcium and Risks of Death and Cardiovascular Disease in Individuals With Chronic Kidney Disease: A Systematic Review and Meta-analysis

Premature cardiovascular disease (CVD), including stroke, peripheral vascular disease, sudden death, coronary artery disease, and congestive heart failure, is a notorious problem in patients with chronic kidney disease (CKD). Because the presence of CVD is independently associated with kidney function decline, it appears that the relationship between CKD and CVD is reciprocal or bidirectional, and that it is this association that leads to the vicious circle contributing to premature death. As randomized, placebo-controlled trials have so far been disappointing and unable to show a survival benefit of various treatment strategies, such a lipid-lowering, increased dialysis dose and normalization of hemoglobin, the risk factor profile seems to be different in CKD compared with the general population. Indeed, seemingly paradoxical associations between traditional risk factors and cardiovascular outcome in patients with advanced CKD have complicated our efforts to identify the real cardiovascular culprits. This review focuses on the many new pieces that need to be fit into the complicated puzzle of uremic vascular disease, including persistent inflammation, endothelial dysfunction, oxidative stress, and vascular ossification. Each of these is not only highly prevalent in CKD but also more strongly linked to CVD in these patients than in the general population. However, a causal relationship between these new markers and CVD in CKD patients remains to be established. Finally, two novel disciplines, proteomics and epigenetics, will be discussed, because these tools may be helpful in the understanding of the discussed vascular risk factors.

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Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle?

Cardiovascular disease begins early in the course of renal decline and is a life-limiting problem in patients with CKD. The increased burden of cardiovascular disease is due, at least in part, to calcification of the vessel wall. The uremic milieu provides a perfect storm of risk factors for accelerated calcification, but elevated calcium and phosphate levels remain key to the initiation and progression of vascular smooth muscle cell calcification in CKD. Vascular calcification is a highly regulated process that involves a complex interplay between promoters and inhibitors of calcification and has many similarities to bone ossification. Here, we discuss current understanding of the process of vascular calcification, focusing specifically on the discrete and synergistic effects of calcium and phosphate in mediating vascular smooth muscle cell apoptosis, osteochondrocytic differentiation, vesicle release, calcification inhibitor expression, senescence, and death. Using our model of intact human vessels, factors initiating vascular calcification in vivo and the role of calcium and phosphate in driving accelerated calcification ex vivo are described. This work allows us to link clinical and basic research into a working theoretical model to explain the pathway of development of vascular calcification in CKD.

Mechanistic Insights into Vascular Calcification in CKD

Background: Retention of uremic toxins in patients with chronic kidney disease (CKD) negatively affects multiple organ systems, including the cardiovascular system, resulting in significant morbidity and mortality. Alleviation of the adverse effects of uremic toxins is an important priority in the management of CKD. Scope: This review focuses on the evidence for the influence of uremic toxins on cardiovascular morbidity and mortality among patients with CKD and slowly developing uremia. The cardiovascular effects of acute kidney injury and rapidly developing azotemia are beyond the scope of this review and will not be discussed. Data on potential treatment options aimed at ameliorating the toxic effects of uremic toxins are summarized. Findings: Uremic toxins are associated with significant cardiovascular morbidity and mortality in patients with CKD. While a number of preclinical studies have detailed these effects, clinical studies directly evaluating cardiovascular outcomes consequent to the presence of uremic toxins have only recently become available. Conclusion: Uremic toxins play an important role in the progression of cardiovascular disease in patients with CKD. Further studies are needed to better characterize the impact of these compounds on cardiovascular outcomes. Beneficial treatments are currently available that, in preliminary studies, appear to neutralize some of the adverse effects of uremic toxins. Large randomized clinical trials are needed to further determine the utility of these varied therapeutic agents.

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Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease.

Background and objectives Patients receiving hemodialysis are at risk of cardiovascular events. A novel blood test ( T 50 test) determines the individual calcification propensity of blood. Design, setting, participants, & measurements T 50 was determined in 2785 baseline serum samples of patients receiving hemodialysis enrolled in the Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) trial and the T 50 results were related to patient outcomes. Results Serum albumin, bicarbonate, HDL cholesterol, and creatinine were the main factors positively/directly and phosphate was the main factor negatively/inversely associated with T 50 . The primary composite end point (all-cause mortality, myocardial infarction [MI], hospitalization for unstable angina, heart failure, or peripheral vascular event [PVE]) was reached in 1350 patients after a median follow-up time of 619 days. After adjustments for confounding, a lower T 50 was independently associated with a higher risk of the primary composite end point as a continuous measure (hazard ratio [HR] per 1 SD lower T 50 , 1.15; 95% confidence interval [95% CI], 1.08 to 1.22; P T 50 was associated with a higher risk in all-cause mortality (HR per 1 SD lower T 50 , 1.10; 95% CI, 1.02 to 1.17; P =0.001), MI (HR per 1 SD lower T 50 , 1.38; 95% CI, 1.19 to 1.60; P T 50 , 1.22; 95% CI, 1.05 to 1.42; P =0.01). T 50 improved risk prediction (integrated discrimination improvement and net reclassification improvement, P P =0.001) of the primary composite end point. Conclusions Blood calcification propensity was independently associated with the primary composite end point, all-cause mortality, MI, and PVE in the EVOLVE study and improved risk prediction. Prospective trials should clarify whether T 50 -guided therapies improve outcomes.

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Blood Calcification Propensity, Cardiovascular Events, and Survival in Patients Receiving Hemodialysis in the EVOLVE Trial.

Background. Patients receiving dialysis therapy for end-stage kidney failure have a high cardiovascular mortality that can only be partially explained by traditional risk factors. Methods. This study was a post hoc analysis of a prospectively gathered data set from a randomized trial comparing outcomes in new haemodialysis patients treated with sevelamer or calcium-containing phosphate binders. Patients were followed from the time of enrollment until death or censor on 31 December 2005. Median follow-up was 3.6 years. Demographics, cardiovascular risk factors, laboratory data, medication use and severity of vascular calcification were available at baseline and over the first 18 months of dialysis. Results. Baseline predictors of mortality included age, creatinine, heart rate, iPTH, C-reactive protein (CRP), coronary and aortic calcium scores and the presence of aortic valve calcification. Over the first 18 months, averages of diastolic blood pressure, BUN, creatinine, albumin, phosphorus, iPTH and CRP were all significantly different between survivors and non-survivors. A stepwise multivariable adjusted Cox regression model demonstrated that low BUN and albumin and high CRP along with the use of calcium-containing phosphate binders (rather than sevelamer) were the strongest predictors of mortality in patients new to haemodialysis. Conclusions.These findings suggest that non-traditional risk factors, such as inflammation and malnutrition measured during the first 18 months of dialysis, are important determinates of survival in new dialysis patients. In addition, the unique risk factor for dialysis patients, the use of calcium-containing phosphate binders, was associated with a higher mortality rate in patients new to dialysis.

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Gerard Smits

Papers

Factors associated with mortality in patients new to haemodialysis